The present invention relates, in general, to probe stabilization relative to movement of a subject. More particularly, the present invention relates to predictive stabilization, of an intracellular probe, relative to the movement of the subject.
Much of our understanding of the function of the brain has come from probing the nervous system at the level of single neurons. With few exceptions, the study of single neurons in behaving animals has been limited to extracellular recordings of action potentials. Action potentials, however, represent only the final, output state of a neuron whose response is essentially determined by the electrical and chemical interactions between smaller, functionally distinct neuronal compartments such as synapses, dendrites, and somata. Nearly all experimental information about the properties and behavior of neurons at this level comes from in-vitro and cell culture experiments. Furthermore, it is known that neuronal integration and firing properties are modulated by neuromodulatory influences and other activities. As a consequence, complete understanding of brain function ultimately requires observation of neuronal compartments and their interactions in intact, live and behaving subject animals.
Problems with mechanical stability make observations of neurons much more difficult in whole-animal preparations than in in-vitro or cell culture preparations. Many structures of interest in neurons are small (on the order of 1 to 10 microns in size), and because electrical and optical probes must be positioned near or inside the cell membrane to function, high quality and long lasting recordings require stable mechanical placement of the probe relative to the tissue. Drift or motion of the electrode or other probe relative to the recorded cell may interfere with good probe penetrations or seals on a neuron. Even when good penetration or seal is achieved, motion may also cause large variations in the recorded signals, degrade the health of the cell, and limit the duration of the recording.
Although a number studies have been published that involve intracellular recordings in anesthetized animals and even awake animals, brain motion makes intracellular recording difficult under even the best conditions. In all these experiments, the essential means of stabilizing the brain is to restrain the head of the animal with a stainless steel plate or pin secured to the cranium. Brain motion in such a head-fixed preparation arises from forces of two origins; first, spontaneous motor behavior of the animal, and second, from periodic physiological processes such as cardiac or respiratory pulsations. These forces may be coupled to the brain in several ways. The cranium and its attachment to the apparatus are both compliant and will move in response to spontaneous and respiratory movements. Forces may also be coupled to the brain through the spinal cord and cerebral spinal fluid. In addition, cardiac pulsations are probably mediated by changes in the volume of cerebral blood vessels. A number of techniques have been developed to permit stable neuronal recordings in the presence of these sources of movement, including draining of the cerebrospinal fluid, mechanical stabilization of the brain or spinal cord, or passive tracking of the probe electrode. Some of these methods, however, accommodate only gross animal movement by restraining the subject, potentially interfering with desired measurements. Other methods may damage fragile brain tissue, or interfere with the subject under study and potentially affect the resulting measurements. In addition, such methods for surface stabilization typically do not account for internal subject movement at a deeper tissue level.
As a consequence, a need remains to provide a method and system for probe stabilization, relative to subject movement, to provide for accurate measurement within a live subject. The method and system should be predictive or active, anticipating subject movement which may otherwise interfere with accurate measurements. In addition, the method and system should not alter or interfere with the physiological states of the subject, and should otherwise minimize contact with the subject tissue, to avoid interfering with the processes under study, to avoid tissue damage, and also to avoid other potential sources of error.
In accordance with the present invention, a method and system are provided for predictive or active probe stabilization, for anticipating subject movement which may otherwise interfere with accurate measurements. In addition, the method and system of the present invention do not alter or interfere with the physiological states of the subject, and otherwise minimizes contact with the subject tissue, to avoid interfering with the processes under study, to avoid tissue damage, and also to avoid other potential sources of error.
In the preferred method and system for predictive probe stabilization, a probe (such as a microelectrode) is mounted on a piezoelectric manipulator and inserted into the subject, so that the probe is moveable in response to a control voltage. A calibrated control voltage is then determined from a known probe displacement, generally by measuring probe impedance as the probe is oscillated (dithered) with a known amplitude and frequency.
A plurality of control voltage parameters, such as finite impulse response filter coefficients, are determined from the calibrated control voltage and from a measured biological function of the subject. In the preferred embodiment, two measured biological functions are utilized: first, cardiac function, as measured by an electrocardiogram; and second, respiratory function, as measured by thoracic pressure. For each of these measured biological functions, a corresponding plurality of control voltage parameters are determined.
The control voltage to the manipulator holding the probe is then generated from the measured biological function and from the plurality of control voltage parameters. When more than one measured biological function is utilized, such as both an EKG and thoracic pressure, then corresponding intermediate control voltages are generated for each measured biological function. The resulting or overall control voltage is then generated as a linear superposition of the intermediate control voltages. The probe is then moved in response to the control voltage, providing stabilization relative to subject movement, and the probe may then be utilized for desired measurements within the subject.
Numerous other advantages and features of the present invention will become readily apparent from the following detailed description of the invention and the embodiments thereof, from the claims and from the accompanying drawings.